: The Type I human interferons, interferon-alpha, beta and -omega (12 Hu-IFN-alpha species, Hu-IFN-beta and Hu-IFN-omega), were among the first cytokines purified, cloned and introduced into the clinical arena. Of these interferons, Hu-IFN-alpha and Hu-IFN-beta are used world wide for treating cancers, viral diseases, multiple sclerosis and other diseases. The efforts of this application flow from work on interferons over the past two decades in the PI's laboratory. The aims of this proposal are to understand the mechanisms by which the various human Type I interferon species produce different biological responses despite the fact that they interact with the same receptor. The overall hypothesis to be tested is that the individual Type I interferons interact with the receptor quite distinctly producing unique patterns of signal transduction that result in the qualitative/quantitative activation or repression of different genes. To achieve the aims the power of DNA microarray technology will be used to identify the genes induced or repressed by the various Type I interferons. These genes will then provide leads to unravel the underlying mechanisms by which these interferons function. The specific aims are: determine the specific genes induced or respressed by each of the Type I interferons with the use of DNA microarrays; analyze the promoters of the genes induced or repressed by the individual Type I interferons to discover new pathways by which they function; determine the qualitative and quantitative differences in signal transduction by the Type I interferons to learn how these differences contribute to differences in activities of the interferons; and assess the role of the Type I interferons in post-transcriptional control of gene expression. This application represents a comprehensive approach to understand the activities and mechanism of action of the Type I interferon family of cytokines. Particular attention is focused on defining the pathways by which each member of the family exhibits unique activities while acting via the same receptor complex. Identification of all the pathways initiated through the Type I interferon receptor will provide an opportunity to develop new interferons and new approaches to treat many diseases.